Cancers are among the leading causes of death in animals and humans. Although many types of chemotherapeutic agents have been shown to be effective against cancers and tumor cells, not all types of cancers and tumors respond to these agents. Current major chemotherapeutic and radiation therapy regimens focus on inducing DNA damage which indiscriminately kills cells, with the hope that the cancerous cells die more quickly than the normal cells. Unfortunately, in many cases the end result is simply prolonged suffering because DNA damage accumulates too quickly in the body for the patient to handle.
Microtubules are an array of fibrous cytoskeleton proteins which control cell strength and molecular movement within the cell. In particular, microtubules are critical to chromosomal movement during cell division. Microtubules are comprised of tubulin subunits which form a diverse array of both permanent and transient structures. The processes of microtubule assembly and disassembly are dynamic and can be affected by various factors including temperature, anti-cancer drug such as colchicines and taxol, and microtubule-associated proteins (MAPs). MAPs are involved in the formation and stabilization of microtubules.
It is hoped that tubulin-binding drugs will offer an alternative to indiscriminate cellular destruction. For mitosis to succeed, the cellular cytoskeleton must be completely rearranged in a particular manner. In fact, it is microtubular motion that is responsible for the actual separation and division of the cellular compartments and the correct distribution of DNA between two cells. Interruption of this process can halt mitosis without any inherent cytotoxic effect, although prolonged interruption of mitosis can lead to apoptosis.
Microtubule formation is a dynamic process which includes polymerization of α- and β-tubulin heterodimers and degradation of tubular polymers. Tubulin-binding drugs interfere with this dynamic process, either by inhibiting microtubule assembly or by over-stabilizing the polymer structure. Microtubule assembly inhibitors are conventionally divided into two classes: colchicines, domain binders such as podophyllotoxin, steganacin, combretastain, and amphethinile; and vinca alkaloid domain binders such as vinblastine, vincristine, maytansinoid, phomopsin A, rhizoxin, dolastatin, and cryptophycin. Taxol microtubule-stabilizing compounds, obtained from natural products, include epothilone, eleutherobin, and discodermolide.
The vinca alkaloids, including vinblastine and vincristine, have been used for treating cancers such as leukemias and lymphomas for a long time, and taxol derivatives have recently been used for treating breast cancers. However, several problems remain with these conventional anti-tubulin drugs. Among these problems are inherent toxicity (especially neurotoxicity) as a side effect, low solubility of the compounds, availability in quantity, and multi-drug resistance. As most of the lead compounds originated from naturally occurring sources (plants, sponges, mollusks, bacteria), chemical modification might be a straightforward approach for improving the activity and properties of the drugs while reducing side effects. Serious efforts have been made to synthesize derivatives of vinca alkaloids, colchicines, taxol and related compounds, but modification of the complicated natural products without adversely affecting utility has so far been difficult.
Many other natural products and their synthetic derivatives are also undergoing clinical testing, particularly combrestatins and cryptophycines, which elicit much interest because of their anti-angiogenic activity and high activity (pM IC50) with respect to multi-drug resistant cells. Another approach is to screen small synthetic molecules to find novel tubulin binders.
Myoseverin, a recently discovered tubulin binder with a novel purine structure, has so far demonstrated a promising ability to surmount the major problems associated with currently available tubulin binding drugs. Myoseverin was originally isolated from a library of 2, 6, 9-substitued purines by virtue of its activity of inducing the reversible fission of multinucleated myotubes into fragments. While myoseverin has an in vitro tubulin depolymerization effect and tumor cell growth inhibition without an apparent cytotoxicity, a transcriptional profiling using DNA microarray and biochemical analysis indicated that myoseverin affects expression of a variety of growth factors, immunomodulation, intracellular matrix remodeling, and stress response genes, implicating the activation of biochemical pathways involved in wound healing. The moderate activity of myoseverin (low μM IC50) remains to be improved by structure-activity relationships.

Although a 2,6,9-substituted purine library is a useful tool for developing better derivatives of myoseverin, there are several flaws. The synthetic scheme confined the modification sequence to substitution at the 9-position (Mitsunobu reaction), the 6-position (1st amination) and the 2-position (2nd amination) because of the reactivity differences among the three positions. This sequence and reaction nature limit the flexibility of diversity generation, especially for the 9- and 6-positions. Additionally, purine, the starting material, is relatively expensive.